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Article

Influence of Various Central Moieties on the Hypolipidemic Properties of Long Hydrocarbon Chain Diols and Diacids

Supporting Info

Daniela C. Oniciu,*^† Jean-Louis H. Dasseux,^† Jing Yang,^‡ Ralf Mueller,^‡ Emil Pop,^‡ Anna Denysenko,^‡ Caiming Duan,^‡ Tian-Bao Huang,^‡ Lianhao Zhang,^‡ Brian R. Krause,^† Sandra L. Drake,^† Narendra Lalwani,^† Clay T. Cramer,^† Brian Goetz,^† Michael E. Pape,^† Andrew McKee,^† Gregory J. Fici,^† Janell M. Lutostanski,^† Stephen C. Brown,^† and Charles L. Bisgaier^†

Esperion Therapeutics, A Division of Pfizer Global Research and Development, 3621 South State Street, 695 KMS Place, Ann Arbor, Michigan 48108, and Alchem Laboratories Corporation, 13305 Rachael Boulevard, Alachua, Florida 32615

J. Med. Chem., 2006, 49 (1), pp 334–348

DOI: 10.1021/jm050650j

Publication Date (Web): December 8, 2005

To whom correspondence should be addressed. Current address: Department of Chemistry, University of Florida, Gainesville, FL 32611-7200. E-mail: oniciu@yahoo.com.

†

Esperion Therapeutics, A Division of Pfizer Global Research and Development.

‡

Alchem Laboratories Corporation.

Abstract

A series of long (11−15) hydrocarbon chain diols and diacids with various central functional groups and terminal gem-dimethyl or -methyl/aryl substituents was synthesized and evaluated in both in vivo and in vitro assays for its potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes, as well as for their effects on lipid and glycemic variables in obese female Zucker fatty rats, Crl:(ZUC)-faBR. The most active compounds were hydroxyl-substituted symmetrical diacids and diols with a 13-atom chain and terminal gem-dimethyl substituents. Furthermore, biological activity was enhanced by central substitution with O, CO, S, SO compared to the methylene analogues and was diminished for compounds with central functional groups such as carbamate, ester, urea, acetylmethylene, and hydroxymethylene.